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ASSAY and Drug Development Technologies

Cell-Based Assay Strategy for Identification of Motif-Specific RANK Signaling Pathway Inhibitors

To cite this article:
Taosheng Chen and Xu Feng. ASSAY and Drug Development Technologies. August 2006, 4(4): 473-482. https://doi.org/10.1089/adt.2006.4.473

Published in Volume: 4 Issue 4: August 31, 2006

Author information

Taosheng Chen, Ph.D.
Lead Discovery and Profiling, Bristol-Myers Squibb Company, Wallingford, CT.
Xu Feng
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL.

ABSTRACT

Osteoclasts, the principal bone-resorbing cells, not only play a pivotal role in skeletal development and maintenance but are also implicated in the pathogenesis of various bone disorders such as postmenopausal osteoporosis, bone erosion in inflammatory conditions, and tumor-induced osteolysis. As a result, several antiresorptive drugs (agents capable of inhibiting osteoclast formation and/or function) have been developed and are widely used to prevent and treat these bone diseases. However, current antiresorptive agents either lack satisfactory efficacy or cause serious side effects in clinical management of these bone disorders. Almost a decade ago, the receptor activator of nuclear factor-κB (RANK) ligand (RANKL) was identified as an essential factor required for osteoclast formation. RANKL exerts the effect by binding to its receptor RANK on osteoclast precursors. RANKL also has a decoy receptor, osteoprotegerin (OPG), which inhibits RANKL function by competing with RANK for RANKL. The unraveling of the critical role for the RANKL/RANK/OPG system in osteoclast biology provides an unprecedented opportunity to develop more effective antiresorptive drugs. Unfortunately, the agents currently under development, such as OPG, RANK-Fc, and anti-RANKL antibodies, all inherit a serious drawback—lack of specificity, due to the involvement of the RANKL/RANK/OPG system in other biological processes such as immune response and mammary gland development. Thus, future efforts may need to shift to explore RANK signaling pathways as more effective therapeutic targets. Here, we review our current understanding of RANK signaling in osteoclasts and then discuss the potential of RANK signaling pathways as therapeutic pathways. Moreover, we further describe a strategy for constructing novel cell-based systems for identifying compounds inhibiting signaling from two recently identified RANK motifs through high throughput screening. We hope that this review will not only provide readers with an update on progress in this area of research but, more importantly, will also serve as a starting point for further discussion and eventual development of new strategies for harnessing the ultimate potential of the RANKL/RANK/OPG system as antiresorptive therapeutic targets.

This paper was cited by:

Development of Cell-Based High-Throughput Assays for the Identification of Inhibitors of Receptor Activator of Nuclear Factor-Kappa B Signaling
Jason W. Ashley,1 Erin M. McCoy,1 Daniel A. Clements,1 Zhenqi Shi,1 Taosheng Chen,2 and Xu Feng1
ASSAY and Drug Development Technologies. Feb 2011, Vol. 9, No. 1: 40-49
Abstract | Full Text PDF or HTML | Reprints | Permissions | Download Metadata
Selective targeting of RANK signaling pathways as new therapeutic strategies for osteoporosis
Joel Jules, Jason W Ashley, Xu Feng
Expert Opinion on Therapeutic Targets. Sep 2010, Vol. 14, No. 9: 923-934
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